The objective of this research is to elucidate genetic mechanisms underlying carcinogenesis in an animal model. The model is hereditary renal carcinoma in the rat. This dominantly inherited predisposition to cancer closely resembles the many such predispositions known in man, but seems to be the only such in an experimental animal. Furthermore, an acquired form of the disease occurs spontaneously or following irradiation or exposure to chemicals, and is pathologically identical to the hereditary form. This model may therefore be relevant for understanding the mechanism of induction of both hereditary and acquired cancers in man. The specific aims are to (1) Determine the nature of the acquired mutation(s) responsible for the occurrence of renal carcinoma in the genetically predisposed rat, (2) Examine the role of the renal carcinoma locus in embryonic development and in radiation carcinogenesis, and (3) Identify and clone the renal carcinoma locus. The procedures to be used will include matings with an unrelated inbred strain, irradiation, surgery, pathologic examination, cytogenetic analysis, and molecular genetic techniques. Southern blotting, polymorphic DNA restriction fragments, molecular cloning, and insertional mutagenesis will be utilized in an attempt to understand the molecular mechanism of carcinogenesis in this model and to clone the renal carcinoma gene.